After early childhood, injury to the central nervous system (CNS) results in functional impairments that are largely irreversible. Within the brain or spinal cord, damage resulting from stroke, trauma, or other causes can result in life-long losses in cognitive, sensory and motor functions, and even maintenance of vital functions. Nerve cells that are lost are not replaced, and those that are spared are generally unable to re-grow severed connections, although a limited amount of local synaptic reorganization can occur close to the site of injury. Functions that are lost are currently untreatable.
Regenerative failure in the CNS has been attributed to a number of factors, which include the presence of inhibitory molecules on the surface of glial cells that suppress axonal growth; absence of appropriate substrate molecules such as laminin to foster growth and an absence of the appropriate trophic factors needed to activate programs of gene expression required for cell survival and differentiation.
By contrast, within the peripheral nervous system (PNS), injured nerve fibers can re-grow over long distances, with eventual excellent recovery of function. Within the past 15 years, neuroscientists have come to realize that this is not a consequence of intrinsic differences between the nerve cells of the peripheral and central nervous system. Remarkably, neurons of the CNS will extend their axons over great distances if given the opportunity to grow through a grafted segment of PNS (e.g., sciatic nerve). Therefore, neurons of the CNS retain a capacity to grow if given the right signals from the extra-cellular environment. Several factors are believed to contribute to the differing growth potentials of the CNS and PNS. These factors include a partially characterized, growth-inhibiting molecules on the surface of the oligodendrocytes that surround nerve fibers in the CNS, but which is less abundant in the comparable cell population of the PNS (Schwann cells). Also, molecules of the basal laminin and other surfaces that foster growth in the PNS but which are absent in the CNS (e.g., laminin). Others are trophic factors, soluble polypeptides which activate programs of gene expression that underlie cell survival and differentiation. Although such trophic factors are regarded as essential for maintaining the viability and differentiation of nerve cells, the particular ones that are responsible for inducing axonal regeneration in the CNS remain uncertain. Reference is made to U.S. Pat. No. 6,551,612 to Benowitz, the teachings of which are incorporated herein by reference.
Inhibitors of Rho A, siRNA directed against Rho A expression, or Rho may enhance nerve re-growth. Clostridia botulinum C3 exotoxin that inhibits Rho A, as do ROCK inhibitors, and siRNA directed against ROCK expression. A recent review article is noted, Brown et al., “Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits,” Circulation Research, 98:730-742 (2006).
Further attention is drawn to Chang et al., “Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis,” Proc Natl Acad Sci U S A., 103(39):14495-500 (2006); and Lin et al., “Acute Inhibition of Rho-kinase improves cardiac contractile function in streptozocin-diabetic rats,” Cardiovasc Res. July 1; 75(1):51-8. Epub (2007). Also noted is Zhang, et al., “Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis,” FASEB J., 20(7):916-25 (2006).
Notable RhoA antagonists are disclosed in U.S. Pat. No. 6,855,688 to McKerracher, “ADP-ribosyl transferase fusion proteins, pharmaceutical compositions, and methods of use.” In this regard, particular mention is made of BA-210, an engineered variant of a naturally occurring bacterial protein known as C3 exoenzyme, corresponding substantially to SEQ. ID NO.: 43 of U.S. Pat. No. 6,855,688 to McKerracher. This is also known as BA-210 and Cethrin.
Previously it was believed that the purines of this invention required intrathecal administration. Reference is made to the administration of [14C] radiolabeled inosine given intraperitoneally and the reported [14C] inosine in the brain and incorporation in brain RNA NAKAGAWA, S., and GUROFF, G., 1973. The uptake of purines by rat brain in vivo and in vitro. J. Neurochem. 20:1143-1149.